Analgesic potentiation

ABSTRACT

A method of producing analgesia by administering α-methyl-3-phenoxybenzeneacetic acid or salt thereof together with acetaminophen and compositions therefor.

This invention is directed to improved methods and compositions forproducing analgesia.

BACKGROUND OF THE INVENTION

One of the long existing primary goals of medicine is the relief ofpain. Relief is sought most generally by the administration of analgesicdrugs which produce a state of decreased awareness of the sensation andincrease of the pain threshold.

Almost all potent analgesics evoke reactions other than the relief ofpain. Some of the reactions are gastrointestinal disturbances, nausea,constipation and vomiting. Among the more serious of the side reactionsand one frequently found in analgesic drugs is respiratory depression.Thus, in the use of analgesics in man, considerations other than theprimary effect (analgesia), must be made and drugs for pain relief aresought which have maximum analgesic effect accompanied by minimum sidereactions. It is difficult to satisfy these requirements with a singlechemical entity since generally a potent analgesic has accompanyingserious side reactions while a drug with little or no side effects aregenerally less effective as an analgesic.

Thus, there is a continuing search for a combination of two or moredrugs whereby the total quantity of drug can be reduced and which can beemployed in such proportions as to produce maximum analgesic effect withlittle or no side effects. When one or both of the components of acombination is known to possess pain-relieving properties but theseproperties are increased many fold, the net effect of the combination iscommonly referred to as "potentiation".

Acetaminophen (p-acetaminophenol) is recognized as an analgesic agentwith useful antinociceptive properties. However, in certain instances,high doses must be employed to effectively reduce pain.α-Methyl-3-phenoxybenzeneacetic acid is known by the generic name of"fenoprofen" for use as an anti-inflammatory and analgesic agent.However, the effect of the combination of these drugs on the analgesicproperties was not known prior to our work.

STATEMENT OF THE INVENTION

The present invention concerns an improved method of producing analgesiamade possible by the discovery that a potentiation of analgesic orantinociceptive properties of α-methyl-3-phenoxybenzeneacetic acid orits salt is produced by administration with acetaminophen in specificproportions. The use of the combination in the suppression of pain isunexpectedly much greater than that which would result from simply theadditive effect of the components.

DESCRIPTION OF THE INVENTION

The novel and unexpected superior analgesic properties may be achievedby the simultaneous or sequential oral administration of (1) anα-methyl-3-phenoxybenzeneacetic acid compound, said compound beingα-methyl-3-phenoxybenzeneacetic acid represented by the formula ##STR1##or a therapeutically acceptable salt thereof and (2) acetaminophen. Thetherapeutically acceptable salts are those obtained from appropriateorganic or inorganic bases. Preferred salts include those of sodium,potassium, calcium, and the like.

The efficacy of the novel combination in producing antinociceptiveproperties is particularly seen in acetylcholine bromide abdominalconstriction assay of Collier et al [(Brit. J. Pharmacol. Chemotherap.32, 295-310 (1968)] sometimes referred to as the "mouse writhing test".In the test, mice are dosed with test drug combinations and thereafterinjected interperitoneally with acetylcholine bromide and the abdominalconstriction responses or block of abdominal constriction responses areobserved and compared with control operations.

More specifically, in an operation carried out substantially asdescribed by Collier and co-workers, nonfasted albino mice weighing18-24 grams were dosed with combinations of one test drug in selectedfixed doses together with a second test drug at variable doses for eachfixed dose. These were compared with animals dosed with (a) the firsttest drug at the same doses used in combination but employing salineinstead of the second drug, (b) the second test drug at the doses usedin combination but employing saline instead of the first drug, and (c) asaline control containing no drug. Each of the drugs, when separatelyemployed, were found to be inactive in the acetylcholine bromideabdominal constriction test at the test dose level.

In carrying out the tests, the test compositions and the controlcompositions both with and without drugs were administered orally to thetest mice. After about 30 minutes the mice were injectedintraperitoneally with acetylcholine bromide and the abdominalconstriction responses compared (corrected for saline responses asnecessary). The results are expressed as percent block.

When the percent block of abdominal constriction observed with the fixeddose was 5 percent or more, the percent block observed with each of thecombination dosage levels was corrected with respect to the percentblock observed with a fixed dose drug using Abbott's formula for naturalmortality.

Likewise, when the response to acetylcholine bromide in the salinecontrol group was 95 percent or less, the response observed with each ofthe variable dosage levels used in the ED₅₀ determination was similarlycorrected using Abbott's formula for natural mortality. ED₅₀ and 95percent confidence limits were calculated according to Finney's probitanalysis procedure. (Finney, D. J. 1964, Probit Analysis, SecondEdition, University Press, Cambridge.) All ED₅₀ for a given comparisonwere calculated using a common slope following a test for parallelism.All paired dose response curves were found to be parallel.

Employing the above-described procedures, potentiation of the analgesicproperties of an α-methyl-3-phenoxybenzeneacetic acid compound(hereinafter sometimes referred to as "fenoprofen compound") byacetaminophen may be demonstrated. The property is illustrated employingthe sodium salt of fenoprofen but it is to be understood that it is notlimited thereto.

Non-fasted male albino mice weighing 18-24 grams were dosed initiallyper os (p.o.) with fenoprofen sodium at various doses and with saline asseen in Tables IA and IB and fifteen minutes later with acetaminophen at25 mg/kg or at 50 mg/kg. All dose levels of test drug and saline controlwere given as and are expressed as per os. Twenty mice were employed foreach dosage level. As controls, a similar number of mice were dosed with(a) acetaminophen (25 mg/kg) plus saline (10 ml/kg) or acetaminophen (50mg/kg) plus saline (10 ml/kg) and (b) double dose of saline (10 ml/kg).Fenoprofen sodium was administered as an aqueous solution. Acetaminophenwas administered as an aqueous suspension.

Thirty minutes after administration of fenoprofen sodium (and 15 minutesafter administration of acetaminophen), the mice were injectedintraperitoneally (i.p.) with 5.5 mg/kg of acetylcholine bromide andobserved for the presence or absence of the abdominal constrictionresponse. ED₅₀ values were determined from the observed values applyingwhere pertinent corrections previously discussed. The results are seenin Tables IA and IB.

(Where "mg/kg" or "ml/kg" is employed, "kg" is in reference to bodyweight.)

                                      TABLE I-A                                   __________________________________________________________________________                 FENOPROFEN                                                                    SODIUM   OBSERVATION                                                                             PER- FENOPROFEN                                            DOSE     Number Responding                                                                       CENT ED.sub.50 (95% CL***)                    TREATMENT    (mg/kg)  Number Injected                                                                         BLOCK                                                                              (mg/kg)                                  __________________________________________________________________________    Fenoprofen NA                                                                              10        3/20     85(82)*                                                                            3.4(2.1-5.5)                             + Saline(10 ml/kg)                                                                         5         6/20     70(65)*                                                    2        11/20     45(35)*                                                    1        18/20     10(0)*                                        Fenoprofen NA +                                                                            10        4/20     80(73)**                                                                           3.7(1.8-7.6)                             Acetaminophen, 25 mg/kg                                                                    5         6/20     70(60)**                                                   4         7/20     65(53)**                                                   2        14/20     30(7)**                                       Acetaminophen, 25 mg/kg                                                                    --       15/20     25(12)                                        + Saline, 10 ml/kg                                                            Saline, 10 ml/kg                                                                           --       17/20     15(--)                                        + Saline, 10 ml/kg                                                            __________________________________________________________________________     *Percent block corrected for saline response                                  **Percent block corrected for fenoprofen + saline response                    ***Confidence limits                                                     

                                      TABLE I-B                                   __________________________________________________________________________                 FENOPROFEN                                                                    SODIUM   OBSERVATION                                                                             PER- FENOPROFEN                                            DOSE     Number Responding                                                                       CENT ED.sub.50 (95% CL***)                    TREATMENT    (mg/kg)  Number Injected                                                                         BLOCK                                                                              (mg/kg)                                  __________________________________________________________________________    Fenoprofen   10        5/20     75(69)*                                                                            4.6(2.48-8.37)                           + Saline (10 ml/kg)                                                                        5         7/20     65(57)*                                                    2.5      12/20     40(25)*                                                    1.0      14/20     30(13)*                                       Fenoprofen + 10        1/20     95(93)**                                      Acetaminophen, 50 mg/kg              1.93 (0.92-3.77)                                      5         4/20     80(82)**                                                   2.5       8/20     60(43)**                                                   1.0      12/20     40(15)**                                      Acetaminophen, 50 mg/kg                                                                    --       14/20     30(13)                                        + Saline, 10 ml/kg                                                            Saline, 10 ml/kg                                                                           --       16/20     20(--)                                        + Saline, 10 ml/kg                                                            __________________________________________________________________________     *Percent block corrected for saline response                                  **Percent block corrected for acetaminophen + saline response                 ***Confidence limits                                                     

The foregoing results illustrate the potentiation of the analgesic orantinociceptive properties of a fenoprofen compound by acetaminophen.

The process of the present invention, namely, a method of producinganalgesia, comprises orally administering to subjects, i.e., human andother warm-blooded animals suffering from pain, a fenoprofen compoundand acetaminophen in amounts sufficient to have an antinociceptiveeffect. The agents may be administered simultaneously or sequentiallyand either agent may be administered first. By the administration of theamounts of the agents as hereinafter set forth, an antinociceptiveinteraction between the drugs is achieved which is wholly unexpectedfrom the known properties of the components. The active agents may beadministered with or without carrier. One method of administration is byuse of compositions in unit dosage form which provides a convenientsimultaneous administration method.

From the foregoing test results on mice and the known dosage ranges ofthe components as applied to man when employed above, it is determinedthat generally from about 1.4 to 2.8 mg/kg of body weight fenoprofencompound may be employed together with from about 3.8 to 7.5 mg/kg ofbody weight of acetaminophen; preferably from about 1.5 to 2.5 mg/kg ofbody weight of fenoprofen compound with from about 4.2 to 7.1 mg/kg ofbody weight of acetaminophen. These amounts when expressed as dosessuitable for man are in the range of from about 84 to 168 milligrams offenoprofen compound and from about 225 to 450 milligrams ofacetaminophen; preferably from about 90 to 150 milligrams of fenoprofencompound and from about 250 to 425 milligrams of acetaminophen.

The outstanding properties are most effectively utilized by use of thenovel pharmaceutical compositions of the present invention. To preparethe pharmaceutical compositions of this invention, a fenoprofen compoundas primary active agent and acetaminophen as a potentiating agent, areintimately admixed with a pharmaceutically acceptable carrier suitablefor oral administration. In preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, includingliquid carriers such as water, glycols, oils, alcohols and the like fororal liquid preparations such as suspensions, elixirs and solutions; andsolid carriers such as starches, sugars, kaolin, calcium stearate, ethylcellulose, etc., including materials which function as lubricants,binders, disintegrating agents and the like for powders, capsules andtablets. Because of their ease in administration, tablets and capsulesrepresent the most advantageous oral dosage form, these compositionsemploy solid pharmaceutical carriers such as the aforementionedstarches, sugars, kaolin and the like, generally with a lubricant suchas calcium stearate. It is especially advantageous to formulate theaforementioned pharmaceutical compositions in dosage unit form for easeof administration and uniformity of dosage. The term "dosage unit form"as used in the specification and claims herein refers to physicallydiscrete units suitable as unitary dosages, each unit containing apredetermined quantity of active ingredient calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. Examples of such dosage unit forms are tablets,capsules, pills, powder packets, wafers, teaspoonsful, tablespoonsfuland the like, and segregated multiples thereof. A dosage unit generallywill contain from about 84 to 168 mg of anα-methyl-3-phenoxybenzeneacetic acid compound as primary activeingredient together with from about 225 to 450 mg of acetaminophen. Thepreferred dosage unit is from about 90 to 150 mg of anα-methyl-3-phenoxybenzeneacetic acid compound together with from about250 to 425 mg of acetaminophen.

The following examples are given to illustrate the novel compositionsand are not to be construed as limiting the invention in spirit or inscope.

EXAMPLE I

1000 hard gelatin capsules, each containing 120 milligrams ofα-methyl-3-phenoxybenzeneacetic acid (fenoprofen) as primary activeingredient and 340 milligrams of acetaminophen as potentiating agent areprepared from the following formulation:

    ______________________________________                                                       GRAMS                                                          ______________________________________                                        Fenoprofen       120                                                          Acetaminophen    340                                                          Starch           250                                                          Lactose          750                                                          Talc             250                                                          Calcium stearate  10                                                          ______________________________________                                    

A uniform mixture of the ingredients is prepared by blending, and usedto fill two-piece hard gelatin capsules. The capsules are suitable to beused for providing satisfactory analgesic effect upon administration tosubjects suffering from pain.

EXAMPLE II

1000 compressed tablets, each containing as the primary activeingredient 100 milligrams of fenoprofen and 400 milligrams ofacetaminophen as potentiating agent are prepared from the followingformulation:

    ______________________________________                                                               GRAMS                                                  ______________________________________                                        Fenoprofen               100                                                  Acetaminophen            400                                                  Starch                   750                                                  Dibasic calcium phosphate hydrous                                                                      5000                                                 Calcium stearate         2.5                                                  ______________________________________                                    

The finely powdered ingredients are mixed well and granulated with 10percent starch paste. The granulation is dried and compressed intotablets.

What is claimed is:
 1. A method for producing analgesia which comprisesorally administering to a subject suffering from pain(1) as primaryactive agent from about 1.4 to 2.5 mg/kg of body weight of anα-methyl-3-phenoxy-benzeneacetic acid compound, said compound beingselected from (a) α-methyl-3-phenoxybenzeneacetic acid represented bythe formula ##STR2## and (b) non-toxic therapeutically acceptable saltsthereof, and (2) as potentiating agent, from 3.8 to 7.5 mg/kg of bodyweight of acetaminophen.
 2. A method for producing analgesia whichcomprises orally administering to a subject suffering from pain(1) asprimary active agent from about 84 to 168 milligrams of anα-methyl-3-phenoxybenzeneacetic acid or a non-toxic therapeuticallyacceptable salt thereof, and (2) as potentiating agent from about 225 to450 milligrams of acetaminophen.
 3. A method according to claim 2wherein the primary active agent is administered in an amount of from 90to 150 milligrams and the potentiating agent in an amount of from 250 to425 milligrams.
 4. A pharmaceutical composition suitable for reducingpain in dosage unit form comprising an effective antinociceptive amountin combination of(1) as primary antinociceptive agent, from about 84 to168 milligrams of an α-methyl-3-phenoxybenzeneacetic acid compound, saidcompound being selected from (a) α-methyl-3-phenoxybenzeneacetic acidrepresented by the formula ##STR3## and (b) non-toxic therapeuticallyacceptable salts thereof, and (2) as potentiating agent, from about 113to 450 milligrams of acetaminophen; wherein said primary and saidpotentiating agents are in admixture with a pharmaceutically acceptablecarrier.
 5. A composition according to claim 4 which comprises perdosage unit (1) from about 90 to 150 milligrams of anα-methyl-3-phenoxybenzeneacetic acid compound and (2) from about 250 to425 milligrams of acetaminophen.
 6. A composition according to claim 4in which the dosage unit form is a tablet.
 7. A composition according toclaim 4 in which the dosage unit form is a capsule.